4WHL

A New Class of Peptidomimetics Targeting the Polo-box Domain of Polo-like kinase 1

4WHL の概要

• エントリーDOI: 10.2210/pdb4whl/pdb
• 関連するPDBエントリー: 4WHH 4WHK
• 関連するBIRD辞書のPRD_ID: PRD_002126
• 分子名称: Serine/threonine-protein kinase PLK1, C6H5(CH2)8-DERIVATIZED PEPTIDE INHIBITOR (3 entities in total)
• 機能のキーワード: polo-like kinase, polo-box domain, inhibitor, peptide derivative, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus: P53350
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 28084.00

構造登録者

Bang, J.K.,Han, Y.H.,Ahn, M.J.,Lee, K.S. (登録日: 2014-09-23, 公開日: 2014-12-03, 最終更新日: 2024-11-06)

主引用文献

Ahn, M.,Han, Y.H.,Park, J.E.,Kim, S.,Lee, W.C.,Lee, S.J.,Gunasekaran, P.,Cheong, C.,Shin, S.Y.,Kim, H.Y.,Ryu, E.K.,Murugan, R.N.,Kim, N.H.,Bang, J.K.
A new class of peptidomimetics targeting the polo-box domain of polo-like kinase 1.
J.Med.Chem., 58:294-304, 2015

PubMed Abstract: Recent progress in the development of peptide-derived Polo-like kinase (Plk1) polo-box domain (PBD) inhibitors has led to the synthesis of multiple peptide ligands with high binding affinity and selectivity. However, few systematic analyses have been conducted to identify key Plk1 residues and characterize their interactions with potent Plk1 peptide inhibitors. We performed systematic deletion analysis using the most potent 4j peptide and studied N-terminal capping of the minimal peptide with diverse organic moieties, leading to the identification of the peptidomimetic 8 (AB-103) series with high binding affinity and selectivity. To evaluate the bioavailability of short peptidomimetic ligands, PEGylated 8 series were synthesized and incubated with HeLa cells to test for cellular uptake, antiproliferative activity, and Plk1 kinase inhibition. Finally, crystallographic studies of the Plk1 PBD in complex with peptidomimetics 8 and 22 (AB-103-5) revealed the presence of two hydrogen bond interactions responsible for their high binding affinity and selectivity.

PubMed: 25347203
DOI: 10.1021/jm501147g

実験手法

X-RAY DIFFRACTION (2.71 Å)